Cathepsin G is a serine protease commonly found in the azurophilic granules of neutrophils and monocytes. Together with elastase and proteinase 3 it belongs to the chymotrypsin family and cleaves extracellular matrix proteins such as elastin, collagen, fibronectin and laminin causing extensive lung tissue damage in the animal.
Cathepsin G also plays a role in blood clotting; in fact, it is involved in an alternative pathway of leukocytes initiation of coagulation, and by activating coagulation factor X and factor V it can cleave and potentially modulate the thrombin receptor and it can activate platelets in vitro. It is also able to convert angiotensin I into angiotensin II with only minor cleavage occurring elsewhere in the molecule.
It was shown that cathepsin G kills bacteria and fungi but this property is not related to its activity, in fact peptides derived from its cleavage showed direct antimicrobial properties. It can also degrade necrotic tissues and is therefore related to several inflammatory diseases like lung emphysema, bronchitis, cystic fibrosis and psoriasis.
The enzymatic activity of cathepsin G is regulated by two types of protein proteinase inhibitors: the so called “canonical” inhibitors and the serpins. The former are relatively small proteins (29-190 amino acids) and are tight-binding reversible inhibitors; among them are Mucus proteinase inhibitor (MPI), eglin c and aprotinin. Serpins are larger proteins (400-450 residues) that form an irreversible complex with their cognate protein due to the formation of a non-hydrolysable acyl bond between the catalytic site of cathepsin G and their reactive site loop. Among serpins 1-antichymotrypsin is the most important: inhibitors of this family are not selective because they are able to bind to and inhibit other chymotripsins. Moreover, their stability and distribution in vivo is affected by their peptidic nature.
Several synthetic inhibitors were found starting from peptidomimetic scaffolds containing 1,2,5-thiadiazolidin-3-one 1,1 dioxide or 1,3-diazetidine-2,4-diones and some of them (particularly those with aromatic side chains) showed a remarkably specific activity for cathepsin G. However, they form non-reversible acyl complexes with the enzyme.
Recently, it was shown that both the full length and cleaved chromosomal DNA is able to bind and inhibit Cathepsin G in vitro and in vivo. A 30 bpDNA fragment tightly binds cathepsin G at physiological conditions and showed a decreasing order of affinity for human neutrophil elastase when compared to proteinase 3 in accordance with their decreasing cationic character.
In particular, EP-775745 discloses oligonucleotide cathepsin G-inhibiting aptamers having a chain length of about 40 nucleotides (and in any case lower than 55 nucleotides) and containing G-pairs repeating units which are useful in the treatment and prophylaxis of inflammatory occurrences and procoagulant conditions.